The Principal Investigator, Dr. Noah Lechtzin, is a promising young investigator who has made a substantial commitment to an academic career in clinical research. His commitment is evident in his pursuit of advanced clinical and research training, including completion of a residency in internal medicine, a fellowship in pulmonary and critical care medicine, and a Master's in Health Science degree in clinical epidemiology. This background provides a solid foundation for him to address challenging questions related to respiratory impairment in amyotrophic lateral sclerosis (ALS). ALS is a devastating fatal neurodegenerative illness in which most patients die from respiratory muscle weakness and associated complications. Despite major efforts, the cause of ALS remains elusive and there is no known cure. While it is recognized that evaluation and management of respiratory failure is critical to the care of ALS patients, there has been relatively little research directed at these problems. The proposed research in this application builds on Dr. Lechtzin's previous research and addresses questions of fundamental importance for the management of respiratory illness in ALS. Non-invasive positive pressure ventilation (NIPPV) is a method to augment alveolar ventilation without the use of an endotracheal airway. Because it has limited risks, NIPPV has rapidly become the standard of care for treating respiratory failure in ALS. However, there is relatively limited data on its use and effectiveness in ALS. The primary objective of this proposal is to understand how NIPPV works, how it is being used, and whether it alters pulmonary function, respiratory symptoms, and quality of life. To this end, we propose three related studies: a) an investigation of the immediate effect of NIPPV on lung compliance; b) a randomized trial of NIPPV in patients with mild respiratory muscle weakness; and c) a cohort study evaluating the effect of NIPPV on quality of life and survival. The principal investigator will be strengthening his knowledge base in the methodology of clinical investigation in a supervised environment guided by exceptionally talented mentors.By combining the resources of the Johns Hopkins Medical Institutions toward the completionof the outlined aims, the Mentored Patient-Oriented Research Career Development Award will provide Dr. Lechtzin the opportunity to expand the skills required for development into an independent clinical investigator.